The hepatic hemoprotein tryptophan 2,3-dioxygenase is the key regulatory enzyme that, through irreversible degradation, normally controls the flux of tryptophan through physiologically relevant pathways. An alternative pathway of tryptophan metabolism also involves the conversion of tryptophan to kynurenine by indoleamine 2,3- dioxygenase, a functionally similar enzyme, which is widely distributed. Although it has been long thought that all hemoglobin and myoglobin have evolved from a common ancestral gene encoding a 14-16 kDa polypeptide, the discovery of indoleamine 2,3-dioxygenase-like myoglobin in abalone, clearly indicates an alternative pathway for myoglobin evolution. This unexpected origin of a myoglobin from indoleamine 2,3-dioxygenase gives some possible insight into the unknown mechanism of indoleamine 2,3-dioxygenase. We have discovered that catalytic amounts of horse heart metmyoglobin and hydrogen peroxide oxidizes tryptophan in a reaction that forms a free radical metabolite of tryptophan with a high spin density the C-3 carbon of the indole ring, which is next to the amino acid side chain. The formation of this free radical metabolite was demonstrated by spin trapping and spin trap-inhibitable oxygen consumption. This tryptophan-dependent oxygen consumption was proposed to be due to the formation of a peroxyl radical resulting from the reaction of the C-3 carbon-centered tryptophan radical with molecular oxygen. - Tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase, tryptophan, AIDS, HIV